Current therapies for Alzheimer disease (AD) provide moderate symptomatic delay at various stages of the disease, but do not arrest the disease progression, and hence, new approaches to the disease management are urgently needed.
In recent years, cerium oxide nanoparticles have been studied as possible potent antioxidant agents that might be able to exert neuroprotective effects. We herein disclose the specific design of a targeted nanoceria-based formulation suitable for AD therapy. The test results obtained indicate the present composition is useful for selective delivery of immunonanoparticles to Aβ (amyloid-beta) plaques with concomitant rescue of neuronal survival and neurite dystrophy. The formulation appears to work by regulating the expression of the BDNF signal transduction pathway.
Oxidative stress and amyloid-beta (Aβ) are considered major etiological and pathological factors initiating and promoting neurodegeneration in Alzheimer's disease (AD) due to the production of free radicals (1-6). To date, use of multiple doses of antioxidants has met with onlyl limited success in abolishing these pathological conditions (7).
Recently, we have discovered that cerium oxide nanoparticles (CNPs) are redox active and biocompatible with both superoxide dismutase (8) and catalase mimetic activity (9). Among the lanthanide series of elements, cerium is distinctive in that it has two partially filled subshells of electrons, 4f and 5d, with many excited substates, resulting in a valence structure that undergoes significant alterations depending on the chemical environment (10-13). A predominant +3 oxidation state on the surface of CNPs is responsible for the nanoparticles' unique antioxidant properties (14, 15). We have shown that a single dose of CNPs prevents retinal degeneration induced by peroxides (16). In vitro, one low dose maintained radical scavenging and protective effects for long durations and multiple insults, suggesting the possibility of its regenerative activity. Therefore, CNPs have been investigated as possible nanopharmacological composition for use against diseases associated with oxidative stress (17-22).
Previously, on an AD human in vitro model, we have confirmed the anti-oxidant properties of CNPs. We have also demonstrated that CNPs do not act as mere anti-oxidant agents, but that they seem regulate signal transduction pathways involved in neuroprotection (23) To date, no early biomarkers for AD have been identified, therefore the appearance of symptoms is indicative of the full-blown disease.
The present disclosure concerns a novel approach wherein a CNP formulation comprises specifically targeted nanoparticles able to direct only to such targets as the brain areas of neurodegeneration and to exert specific effects counteracting neurite dystrophy and inhibiting disease progression. The presently disclosed composition is active at significantly lower dosages and in a single administration as opposed to free nanoparticles. This improvement was achieved by the synthesis of CNPs through the development of an improved method for the conjugation of anti-amyloid β antibodies to the nanoparticles with selective delivery to Aβ plaques and a concomitant increase of neuronal survival.